Virchows Arch (2006) 448: 525531

DOI 10.1007/s00428-005-0095-z
REVIEW ARTICLE
P. Zagorianakou
.
N. Zagorianakou
.
D. Stefanou
.
G. Makrydimas
.
N. J. Agnantis
The enigmatic nature of apocrine breast lesions
Received: 27 March 2005 / Accepted: 12 September 2005 / Published online: 29 March 2006
# Springer-Verlag 2006
Abstract Epithelial cells of fetal breast glandular structures,
at the third trimester of pregnancy (28 weeks), produce
GCDFP-15, in the absence of specific apocrine morphology.
Apocrine epithelium of the breast may be a normal process of
differentiation rather than a result of metaplasia, and it has
been demonstrated that it is estrogen-receptor, progesterone-
receptor and bcl-2 negative, but androgen-receptor (AR)
positive. The significance of AR expression in apocrine epi-
thelium is uncertain. Apocrine epithelium is seen in a wide
spectrum of breast entities, ranging from benign lesions to
invasive carcinoma. Breast cancer accounts 32% of all cancer
cases among women and is the most common type of cancer
in women. Little is known about breast carcinogenesis.
Widely, it is accepted that breast cancer, like most other type
of cancer, is being developed through the accumulation of
genetic aberrations. Apocrine epithelium may reflect in-
stability of the breast epithelium, creating an environment
favouring further oncogenic alterations. In the last decade,
several lines of evidence support the idea that some breast
benign epithelial apocrine lesions are clonal lesions and may
be considered as truly pre-malignant or precursors of breast
carcinoma. Apocrine changes in many cases do not present
any diagnostic difficulty; on the other hand, apocrine pro-
liferations with cytologic atypia can be particularly difficult
and challenging. The purpose of this study is to collect and
highlight the areas of consensus in the literature as well as the
controversial areas concerning the apocrine epithelium of the
breast.
Keywords Breast
.
Apocrine epithelium
.
GCDFP-15
.
Fibrocystic changes
.
Apocrine carcinoma
.
Molecular alterations
Introduction
The apocrine epithelium, from the Greek word +

, is a normal constituent of apocrine glands of

axillary, anogenital skin, eyelids (Moll), ears (ceruminous)
and mammary gland, which consists of cells with eosino-
philic cytoplasm that may contain lipid, iron, lipofuscin,
PAS-positive diastase-resistant granules and a large nucleus
located near the base of the cell (Fig. 1). Fragments of
apical cytoplasm are found in the lumen of these glands.
The apocrine glands develop as epithelial buds from the
outer root sheath of the hair follicles in 5 to 6-month-old
fetuses and continue into late embryonic life as long as new
hair follicles develop [81, 67]. Nevertheless, morphologi-
cally and functionally, the apocrine epithelium is different
from cutaneous, sebaceous and sweat glands [69]. A wide
spectrum of benign and malignant breast lesions contains
epithelial cells that are identical to those that consist the
apocrine glands [37, 48]. Immunohistochemical studies of
benign and malignant breast lesions, showing apocrine
differentiation, report that cells stain positive for androgen
receptors (AR) and lack estrogen receptor (ER), progester-
one receptors (PR) and exhibiting bcl-2 negativity in normal
breast epithelium. Morphological features of apocrine
differentiation were valuable criteria, leading the Patholo-
gists to a benign diagnosis. In a review paper of Love et al.
[49] on fibrocystic disease, the authors are wondering
whether it is reasonable to consider apocrine cells a
pathological phenomenon inasmuch as about 90% of adult
breasts show evidence of them. To date, with the advent of
new technologies, there are compelling molecular data on
these lesions that change the existing concept [40, 80].
P. Zagorianakou
.
N. Zagorianakou
.
D. Stefanou
.
N. J. Agnantis (*)
Department of Pathology, University of Ioannina,
Medical School, University Campus,
P.O. Box 1186, 45110 Ioannina, Greece
e-mail: [email protected]
Tel.: +30-26150-97792
Fax: +30-26510-97858
G. Makrydimas
Department Obstetrics and Gynaecology,
Medical School, University of Ioannina,
Ioannina, Greece
Apocrine markers
The glycoprotein GCDFP-15 (15 kDa), the major compo-
nent of cyst fluid, represents an immunocytochemical
marker of apocrine differentiation that is more reliable than
morphology and the detection of prolactin inducible
protein (PIP)/GCDFP-15 mRNA using in situ hybridiza-
tion (Fig. 2) [27, 59, 48]. It is identical to the gene of the
PIP described in the breast cancer cell line T-47D [77, 57,
33]. The gene is expressed in apocrine glands and in
exocrine organs that have common phylogenetic features
with apocrine glands, such as the bronchial epithelium, the
sweat, salivary and lacrimal glands and the seminal ves-
icles. According to human genome sequencing data, the
GCDFP/PIP is localized at 7q34 [45].
The GCDFP-15 had 95% specificity and 74% sensitivity
as a marker for breast cancer [93, 94] and has been used to
support breast origin in metastatic carcinoma of unknown
primary origin (Figs. 3, 4 and 5). GCDFP-15 is present at a
very low concentration in the plasma of physiological
women and is 140,000 times higher in breast cyst fluid
compared to plasma. The concentration in amniotic fluid of
pregnant women is 7.200 ng/ml [34].
An appreciable discriminating feature between apocrine
cells and normal luminal epithelial cells of the breast is that
while the former expresses AR and lacks ER, PR and bcl-2,
the latter is ER/PR positive and AR negative. The apocrine
cells differ from normal cells not only morphologically but
also biologically [72, 30].
Theories
The origin of apocrine cells has always been a contradictory
issue. Several answers have been given for the presence of
this enigmatic entity. The existence of apocrine cells in the
breast has generally been regarded as a metaplastic process
[86], but this issue has recently been debated [3, 14, 16, 84,
90]. Some authors believe that apocrine metaplasia, in
general, is a terminally differentiated entity [10, 66], others
considered that the apocrine epithelium is a degenerated
epithelium [19, 92]; several authors suggested that these
cells are normal element of the glandular structure of the
breast [27] or a metabolic active epithelium [53]. These
different opinions in the international literature make the
Fig. 2 GCDFP-15, immunostaining in apocrine cysts (DAB 200)
Fig. 3 Intense cytoplasmic immunostaining for GCDFP-15 in: in
situ (Fig. 4), infiltrating (Fig. 5) and metastatic to a lymph node
(Fig. 6) apocrine carcinoma
Fig. 4 Intense cytoplasmic immunostaining for GCDFP-15 in in
situ apocrine carcinoma
Fig. 1 High magnification of apocrine epithelium (H+E400)
526
subject of apocrine epithelium very controversial. Despite
the fact that apocrine changes have been considered a
metaplastic process in the mammary gland, usually
associated with physiological changes in the hormonal
milieu and ageing, there is a strong evidence to suggest that
a part of apocrine changes show molecular alterations using
the existing reliable technology. The molecular changes are
more frequently observed in entities such as apocrine
adenosis and apocrine hyperplasia. We would suggest that,
nowadays, there is overwhelming molecular data that some
of these apocrine changes in proliferative lesions maybe
precursors of malignant transformation [40, 7475, 90, 91].
It would be possible that those data are misleading, but
nevertheless they should be considered mandatory for
further investigation in interesting hot area of breast
research.
Epithelial cells, in some very primitive structures with
no particular distribution, produce CDFP-15 in normal
fetal breast, where their overall number was increased with
gestational age [89]. McKiernan et al. [51] studied the
histology of breast development and reported the existence
of lobular structures, dilated ducts and apocrine secretion.
In the newborn breast, the epithelial cells have an eo-
sinophilic cytoplasm with typical apocrine secretion [70].
It was mentioned in the infant under development that
apocrine metaplasia was observed as part of the post
neonatal involution [38]. Others suggest that apocrine
epithelium belong to entrapped cutaneous apocrine glands
in the area of mammary gland during the process of
development [89].
Apocrine cell-epithelial lesions
Apocrine phenotype is observed in a spectrum of breast
epithelial lesions spanning from benign metaplasia to apo-
crine carcinoma. Apocrine metaplastic epithelium (APM)
is a frequent finding, occurring in approximately 40% of
benign breast biopsies [25]. Apocrine cells in the breast
appear frequently in benign breast lesions such as fibro-
cystic disease (Fig. 6) [17, 2629, 56], papillomas [65],
fibroadenomas [4, 25], sclerosing adenosis [13, 79]
atypical apocrine proliferations, apocrine ductal carcinoma
in situ (DCIS), invasive apocrine carcinoma [47, 1] and
lobular carcinoma [26].
Fibrocystic changes (FCC) are a common finding, and it
is clinically evident in about 50%of women of reproductive
age. In the western countries, 7% of women develop
palpable breast cysts [33]. Single or multiple cysts are the
most prevalent lesion of the female breast [42]. Gross cystic
changes, a common finding in premenopausal women,
generally present as a single cyst. Cysts are thought to arise
through obstruction of the ducts. There are two types of
cysts. Type I cysts (apocrine or secretory) have high levels
of potassium ions (Na
+
/K
+ ratio
<3), large concentrations of
steroid hormones, epidermal growth factor and gross cystic
disease fluid protein, and it is thought to be under androgen
regulation [36, 7, 52]. Apocrine changes are prevalent in
flat to cuboidal cells lining type I cysts. Type II cysts with
content Na
+
/K
+ ratio
>3 are lined by flattened epithelium.
The morphological presentations of hyperplastic changes
include papillary or micropapillary lesions composed of
apocrine cells.
However, several follow-up studies have suggested that
apocrine epithelium may be a predictor of the subsequent
development of malignancy [35, 60].
Several reports have assessed the relation between
palpable breast cysts and breast carcinoma and suggested
that there is an increased risk of breast carcinoma, which
ranges from 1.7 to 7.5 times [68, 17, 8, 11, 6]. Haagensen
et al. found a fivefold-increased incidence of carcinoma
associated with papillary apocrine metaplasia in fibrocystic
changes, although this fact has subsequently been ques-
tioned [12, 35]. Dixon, et al., has shown no significant
association between cyst type and breast-cancer risk [20].
Dupont and Page [22], in their long-term follow-up study
of women with benign breast lesions, found an increased
relative risk only of 1.7 in cases without complications. A
slightly elevated relative risk of 2.4 for subsequent de-
velopment of malignancy has been noticed for those cases
with complex papillary lesions [61].
Fig. 5 Intense cytoplasmic immunostaining for GCDFP-15 in
infiltrating apocrine carcinoma
Fig. 6 Apocrine cysts in a breast with fibrocystic changes (H+E
100)
527
The presence of focal apocrine metaplasia within epi-
thelial breast proliferations is generally considered as an
important indicator in the histopathologic diagnosis of
benignity [78].
The definition of apocrine metaplasia is based on the
following criteria: (a) eosinophilic cytoplasm with fine
granularity, (b) large and moderately vesicular nuclei with
an occasional prominent red nucleoli and (c) sporadic
presence of apical snouts [83, 58].
Borderline apocrine lesions are classified into two cat-
egories: atypical apocrine adenosis and atypical ductal
hyperplasia of apocrine type [46]. In 1963, Papanicolaou
[63] used the descriptive term of non-malignant atypia
for apocrine cells, the individual cells or cellular clusters
that show enlargement, metaplasia, engulfment and vacu-
olation, which is often extreme.
OMalley et al. [58] used morphologiccytologic criteria
and extent criteria. Apocrine lesions that measured less
than 8 mm were called benign. The human breast epi-
thelium is a dynamic entity that is remodeled under the
influence of sex hormones and growth factors. This dy-
namic ability of breast cells reflects instability of the breast
epithelium, creating an environment susceptible to carci-
nogenesis. Breast lesions with APM epithelium appear to
demonstrate abnormal oncoprotein and apoptosis-related
protein expression associated with a high proliferation rate
[74]. Increased cellular and architectural atypia may in-
dicate an increased risk of developing apocrine carcinoma
[97].
Apocrine adenosis (AA) is a rare breast lesion, which
is characterized as sclerosing adenosis associated with
marked apocrine metaplastic changes [79, 13]. Simpson et
al. [79] identified in a retrospective study of 10,000 be-
nign biopsies of 55 cases of apocrine adenosis.
AA has been misdiagnosed as carcinoma due to the
cytologic atypia of the apocrine cells, and it is occasionally
so florid that it gives rise to a distinct mass, which can be
mistaken clinically for cancer [93, 76]. Wells et al. [93]
have suggested that apocrine adenosis may be a precan-
cerous lesion, mainly on the basis of the expression of c-
erbB2 protein.
Apocrine adenoma is another rare breast neoplasm,
composed exclusively of apocrine cells, which is sharply
demarcated and shows back-to-back glands with papillary
fronds projecting into the lumina. This rare lesion should
be distinguished from well-differentiated apocrine carci-
noma [10, 5].
Neoplastic transformation may occur in metaplastic
epithelium. Cancer of the bladder, stomach, lung and cer-
vix have their origin in these metaplastic areas. The
metaplastic epithelium returns to the normal epithelium
when the stimulus is removed. The stimuli leading to
metaplasia could also lead to carcinogenesis of the meta-
plastic epithelium. The stimulus for apocrine metaplasia is
unknown. Chemicals, vitamins, and growth factors play a
significant role in metaplasia [18].
It is well known that some hyperplastic breast lesions
might actually be clonal in origin. The detection of allelic
imbalances in ductal hyperplasia and papillomas suggested
that these lesions might be neoplastic (monoclonal) rather
than hyperplastic (polyclonal) proliferations [44, 87].
The findings of molecular alterations in benign prolif-
erative apocrine lesions such as APM, apocrine hyperplasia
and apocrine adenosis support the idea that these lesions
are clonal. Several authors using comparative genomic
hybridization demonstrated loss of 1p, 2p, 10q, 16q, 17q
and 22q and gain of 1p, 2q and 13q [40], and analyses of
heterozygosity/allelic imbalance have demonstrated that
the average number of genetic changes (overall gains and
losses) at 1p, 11q, 13q, 16q and 17q is frequent event in
APM, AA and apocrine hyperplasia [73, 75, 89, 90].
Two studies have shown aneuploidy in apocrine meta-
plastic cells [39, 88]. Abnormal oncogene expression has
been discovered in apocrine metaplastic epithelium by
Papamichalis et al. [62] using an antibody to c-myc
oncoprotein. Agnantis et al. [2] studied 12 cases of apo-
crine breast carcinomas, 5 of these cases were associated
with benign apocrine lesions, either adjacent to the tumor
or distant, and demonstrated the expression of c-myc p62
and GCDFP-15 (Agnantis et al., unpublished data pre-
sented at 4th International Symposium and Workshop,
Problmes Actuels de Pathologie Mammaire, Paris De-
cember 58, 1988). Four years later, Agnantis et al. [2]
reported that the great majority of complex cystic disease
shows elevated expression of both c-myc p62 and ras p21,
when associated with apocrine metaplastic papillary
proliferations.
Apocrine DCIS-apocrine carcinoma
Apocrine lobular in situ neoplasias and apocrine ductal in
situ carcinomas are well-defined entities [26, 83, 1]. The
consensus conference on the classification of DCIS
recognized apocrine DCIS as a special variant, which is
characterized by remarkable proliferation of apocrine cells
showing nuclear pleomorphism with enlarged nuclei,
multiple prominent nucleoli and irregular nuclear mem-
branes. The presence of necrosis is not mandatory for the
diagnosis of DCIS [85]. On the other hand, based on the
World Health Organization (WHO) histological classifica-
tion of breast tumors of 2003, apocrine DCIS is not
recognized as a distinct entity, but is incorporated in the
morphological changes of DCIS [84]. Apocrine differen-
tiation may be present in up to 50% of the cases of DCIS,
although Eusebi et al. [27] consider it an infrequently rec-
ognized phenomenon. Simpson et al. [80] supported that
the common assumption at Diagnostic Pathology that a
proliferative lesion with the pattern of micropapillary DCIS
is thought to be benign because it has abundant pink
cytoplasm that may be erroneous. There are substantial
molecular data that some of these lesions may be the
precursors of high grade DCIS and invasive cancer.
The recognition of apocrine carcinoma as a special type
of breast carcinoma continues to be a subject of debate, due
to the lack of uniform criteria for reliable recognition by
light microscopy. Apocrine carcinoma is an unusual variant
of breast carcinoma, probably of ductal origin or sweat
528
gland duct [42, 28]. The incidence of apocrine carcinoma
varies from 0.3 to 4% of all cases. Rosen [69] stated that the
term should be used for neoplasms as composed entirely or
predominantly of apocrine-type epithelium [4, 54].
On the other hand, scattered areas or focal apocrine cells
were found in about 60% of carcinomas of no special type
(ductal, NST) [35]. Eusebi and Azzopardi [25] suggested
that the basic criteria for a diagnosis of apocrine carcinoma
should include neoplastic cells with copious, variably
granular eosinophilic cytoplasm and vesicular nuclei with
prominent nucleoli. Three years later, Haagensen et al.
[35] proposed the following criteria: large size of the
neoplastic cells, acidophilia of the cytoplasm and cyto-
plasmic snouts projecting into the lumina of glands.
The degree of atypia varies, and tumor cells may occa-
sionally present with bizarre, multilobulated nuclei con-
taining multiple nucleoli [29]. The nuclear chromatin is
irregular and often condensed along the periphery of the
nuclear membrane. Most apocrine carcinoma cells are
recognized as grade 2 or 3 according to a modified Scarff
BloomRichardson grading [23]. Cytologic smears of
apocrine carcinoma yield abundant, pleomorphic tumor
cells. The cells occur singly and with syncytia in the
background of numerous degenerated apocrine cells, and
characteristic cell detritus are found. The cells have
abundant basophilic to eosinophilic granular cytoplasm.
The nuclei are enlarged and vesicular and are centrally or
eccentrically located. The nuclei measure > or = 12 m in
diameter, when compared to benign apocrine metaplasia
with atypia. The nucleoli are prominent and may be
multiple [21, 32, 95, 96]. Apocrine carcinoma is a rare
variant of breast carcinoma that occurs in advanced age, the
peak incidence being the sixth and seventh decades of life
[2]. Apocrine carcinoma occurs in both females and males
and manifests as a solid or cystic mass ranging from 0.5 to
5 cm in diameter [9]. Mammographic presentation did not
present differences from those of ductal carcinomas [31].
Apocrine carcinomas are mostly variants of ductal car-
cinomas, but areas of apocrine differentiation have been
reported in pleomorphic lobular carcinoma [26, 41, 82] and
papillary [64]. They are predominantly ER and PR
negative, but AR positive [30, 71]. On the other hand,
3591% of breast cancers are also reported to express AR
[43, 55, 24, 15]. The prognosis of apocrine carcinoma is the
same with other types of breast carcinoma. Matsuo et al.
[50] have reported that the positive rate of p53, HER2 and
BCL-2 in apocrine carcinoma was almost the same as that
of non-apocrine carcinomas.
Conclusions
In conclusion, we propose the term apocrine precursor
cells, for GCDFP-15 positive breast epithelium cells,
without apocrine morphology. Based on the existing recent
molecular data, we conclude that benign proliferative apo-
crine lesions showing molecular alterations could be
considered as clonal and precursors of malignant transfor-
mation. We believe that more clinical follow up and molec-
ular data are needed for a comprehensive knowledge of the
natural history of these lesions.
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